tbuckley/cabot-search huggingface dataset:
Treatment of alpelisib induced hyperglycemia with sodium-glucose cotransporter-2 inhibitors: A single institution experience.
Authors: Emily Brugioni, Timothy J. Pluard, Elizabeth Jane Cathcart-Rake, Kensey Gosch
Journal: Journal of Clinical Oncology (2022)

e13041 Background: PIK3CA mutations occur in about 40% of patients with HR+/HER2- breast cancer. The phase III SOLAR-1 trial demonstrated prolonged progression-free survival with alpelisib and fulvestrant compared to fulvestrant alone among patients with HR+/HER2-/ PIK3CA mutant advanced breast cancer previously treated with endocrine therapy. Hyperglycemia was seen in 64% of patients treated with alpelisib and fulvestrant and was treated with metformin. Inhibition of PI3Kα leads to an on-target effect of hyperglycemia and a secondary hyperinsulinemia. This rebound hyperinsulinemia may lead to escape PI3K pathway activation in breast cancer progression via the insulin and IGF1pathways. Concurrent administration of SGLT2 inhibitors may abrogate the PI3K pathway activation effect and delay disease progression. This study reports time on treatment with alpelisib and PFS among patients who received an SGLT2 inhibitor with alpelisib. Methods: A retrospective review of all metastatic breast cancer patients treated with alpelisib was completed from 8/2019 to 5/2021 at the Saint Luke’s Koontz Center for Advanced Breast Cancer. Results: This review included 22 female patients, 11 received an SGLT2 inhibitor for treatment related hyperglycemia (A+SGLT group) and 11 who received metformin/other diabetic agents (A group). Baseline characteristics were not significantly different between the two groups: median age 63, BMI of 29.1, hemoglobin A1C of 6.3 and fasting blood glucose of 119.1mg/dl. PIK3CA mutations included H1047X (40.9%), E545X (31.8%), E542K (13.6%), other (13.6%). The median number of prior treatments for MBC was 3 (range 1-5). Prior treatments included aromatase inhibitors: 100%, fulvestrant: 77%, CDK 4/6 inhibitors: 82%, everolimus: 32% and chemotherapy: 68%. Hyperglycemia grade 2+ was seen in 72.7% of patients. There were no significant differences between the two groups for emergency room visits, hospitalizations, or endocrinology referrals related to hyperglycemia. Median time to initiation of an SGLT2 inhibitor was 13 days following the first dose of alpelisib. PFS was longer in the A+SGLT compared with the A group with a median time to progression of 6.1 months and 3.9 months respectively (HR 0.51; 95% CI 0.16 to 1.63; p = 0.39). Time on treatment was significantly longer for A+SGLT group compared with the A group, with a median time on treatment of 5.8 months, compared with 3.0 months (HR 0.32; 95% CI 0.11 to 0.92; p = 0.03). The primary reason for discontinuation of alpelisb was disease progression in 73%, with no statistically significant difference in the reason for discontinuation between the groups. Conclusions: This study supports a potential clinical benefit of an SGLT inhibitor along with alpelisib in allowing for a longer time on treatment, without significant adverse events. It also suggests a possible favorable impact on PFS for the combination.
Feasibility of systematic screening for unmet social determinants of health (SDoH) needs and associated resource utilization in ambulatory oncology.
Authors: Ashley Odai-Afotey, Ellana Haakenstad, Bridget A. Neville, Stuart R. Lipsitz, Sunyi Zhang, Nadine Jackson McCleary
Journal: Journal of Clinical Oncology (2022)

6535 Background: Addressing unmet SDoH needs may reduce interruptions to cancer care caused by ED visits and hospitalizations (EDH). We aimed to determine feasibility of systematic screening for unmet patient-reported SDoH needs within a large tertiary academic comprehensive cancer center and association of unmet needs with EDH. Methods: We conducted a cross-sectional analysis of SDoH needs among new oncology patient (pts) consults from 5/15-9/21 at Dana-Farber Cancer Institute (DCFI). Pts completed an intake questionnaire including demographics, disease, and SDoH needs of financial distress, health literacy/numeracy, social isolation on a dichotomous or 5-point Likert scale. We ran bivariate and multivariable models on the association between demographics, SDoH and EDH within 30 days of consult using robust generalized estimating equations controlling for clustering by consult provider. Results: 125,997 unique new consults were seen from 5/15 – 9/21 of which 20,913 completed the intake questionnaire and were alive at 30 days after consult. Respondents were age 40-64 (50%), female (60%), non-Hispanic (84%), White (90%) and English speaking (97%), and 7% had an EDH within 30 days of consult. The most reported SDoH need was limited health numeracy (26%). In bivariate analysis, factors associated with ED visits were: non-English language, lung or GU/GYN cancer, living &gt; 25 mi from DFCI and limited health literacy and numeracy (all p &lt; 0.05). Demographics associated with hospitalizations included: White race and English as a primary language (EPL) (both p &lt; 0.05). Multivariable analysis showed female gender (OR 1.53, p &lt; 0.01), lung (OR 3.22*) and GU/GYN (OR 2.21*) (p &lt; 0.05 for both) cancer, and living &gt; 25 mi from DFCI (OR 2.50, p &lt; 0.0001) were associated with increased likelihood of ED visit while EPL (OR 1.80, p &lt; 0.05) and GU/GYN (OR 1.65, p &lt; 0.01*) cancer were associated with increased likelihood of hospitalization. Conclusions: It is feasible to systematically screen for unmet SDoH which are associated with increased frequency of ED visits. Differences in characteristics associated with ED vs. hospitalization could indicate possible bias or suggest SDoH needs as a reason for avoidance of costly medical care. Further study will expand SDoH screening and measure impact of resource matching to reduce disruptions to cancer care. [Table: see text]
Navitoclax plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis: Preliminary safety and efficacy in a multicenter, open-label phase 2 study.
Authors: Francesco Passamonti, James M. Foran, Anand Tandra, Valerio De Stefano, Maria Laura Fox, Ahmad Hatem Mattour, Mary Frances McMullin, Andrew Perkins, Gabriela Rodriguez-Macias, Hassan Sibai, Qin Q. Qin, Jalaja Potluri, Jonathan B. How
Journal: Journal of Clinical Oncology (2022)

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-X L and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 10 9 /L or &gt;150 × 10 9 /L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR 35 ) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS 50 ), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm 3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%]). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR 35 was achieved by 52% of evaluable pts at wk 24 (SVR 35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR 35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR 35, TSS 50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]
Efficacy of liposomal doxorubicin in patients with intra- and extra-abdominal desmoid fibromatosis.
Authors: Rodney Dixon Dorand, Sean Cohen, Vicki Leigh Keedy, Scott C. Borinstein, Rashmi Chugh, Elizabeth J. Davis
Journal: Journal of Clinical Oncology (2022)

11581 Background: Desmoid tumors (DT) or aggressive fibromatosis are rare growths of fibroblastic connective tissue that can be locally aggressive but without metastatic potential. Most cases are sporadic, but 5-20% of cases are associated with Familial adenomatous polyposis (FAP). Despite numerous systemic options, optimal choice is unclear, and there is a paucity of studies comparing efficacy based on tumor site. Liposomal doxorubicin (LD) can be an appealing option for DT patients (pts) given its favorable schedule and toxicity profile. In this study, we compared outcomes in pts with intra-abdominal (IA) and extra-abdominal (EA) DT who received LD. Methods: We identified pts with DT who were treated with LD between 1/2010 - and 2/2022 at two sarcoma centers. Tumor and pt characteristics and outcomes were clinically (symptom improvement) and radiologically (RECIST 1.1) assessed. Results: 40 pts with DT treated with LD were identified; 58% female and 42% male. Pt characteristics and outcomes are summarized in Table 1. Primary tumor site was IA in 21 (53%) pts. FAP was present more commonly in pts with IA vs EA DT, 8/21 (43%) and 4/19 (21%), respectively. In the IA cohort, LD was given as first (15/21, 71%), second (10%) or third (19%) line therapy. LD was used more commonly as a later line in the EA cohort with 16%, 52%, 16%, and 16% receiving it in first, second, third, and fourth lines, respectively. 37 pts were evaluable for response. Response rate in the IA cohort treated in first-line was 50% (8 of 16) and 10 of 12 evaluable pts had symptomatic improvement. No first-line responses were seen in the EA cohort. As later lines of therapy, 7/12 pts had disease control in the second line, 6/8 pts in the third line, and 1/2 pts in the fourth line with LD in the IA cohort. 1 patient had fourth line response to LD in the EA cohort. Disease control rate with LD was 72.5% across all pts. Reasons for early discontinuation of LD included progression or lack of symptom improvement (20%), allergic reaction (12.5%), adverse effects (7.5%), or infection (2.5%). No acute or long-term cardiotoxicity was reported. 2 pts had no signs of recurrence or symptoms at follow-up, 33 pts were alive with symptomatic DT, 1 patient died from disease, and 3 were lost to follow-up. Conclusions: In our study, LD provided tumor response, disease control, and symptomatic improvement regardless of location or prior therapy, with responses most frequently seen in IA DT in first line setting. Further studies should include comparison of efficacy, adverse effects, and patient-reported outcomes while accounting for tumor location and line of therapy. [Table: see text]
Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).
Authors: Gerald Steven Falchook, Antoni Ribas, Diwakar Davar, Zeynep Eroglu, Judy S. Wang, Jason J. Luke, Erika P. Hamilton, Brian Di Pace, Tianli Wang, Srimoyee Ghosh, Arindam Dhar, Theo Borgovan, Angela Waszak, Patricia LoRusso
Journal: Journal of Clinical Oncology (2022)

2504 Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t 1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]
MUC family influence on acute lymphoblastic leukemia in Native American populations from Brazilian Amazon.
Authors: Angélica Leite de Alcântara, Lucas Favacho Pastana, Laura Patrícia Albarello Gellen, Giovana Miranda Vieira, Elizabeth Ayres Fragoso Dobbin, Thays Amâncio Silva, Esdras Edgar Batista Pereira, Williams Fernandes Barra, Juliana Carla Gomes Rodrigues, Marianne Rodrigues Fernades, Paulo Pimentel Assumpção, João Farias Guerreiro, Sidney Emanuel Batista dos Santos, Ney Pereira Carneiro dos Santos
Journal: Journal of Clinical Oncology (2022)

e19025 Background: The MUC family includes several genes previously associated with carcinogenesis and it is associated with solid neoplasms such as those of the gastrointestinal tract. As far as we are aware, there are no studies relating MUC genes to acute lymphoblastic leukemia (ALL), and this type of cancer is more frequent in the Amerindian population, which has been understudied. Therefore, the present work aimed to investigate the MUC family exome in Amerindian individuals from Brazilian Amazon, in a sample containing healthy Native Americans (NAM) and indigenous with ALL, comparing the frequency of polymorphisms between these two groups. Methods: The population was formed by 64 Amerindians from the Brazilian Amazon from 12 different ethnic groups, 5 of whom were diagnosed with ALL. We analyzed 16 genes from the MUC family (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, MUC20, MUC21) and found a total of 1858 variants. Results: After the quality filter, only 743 variants remained. Among them, we compared the frequency of each polymorphism in the LLA vs NAM group, which led to 77 variants with a significant difference, and, among these, we excluded those with LOW impact, resulting in 63. The 63 polymorphisms were distributed in 9 genes, concentrated especially in MUC 19 (n = 30) and MUC 3A (n = 18). Finally, 11 new variants were found in the NAM population. Conclusions: This is the first work with a sample of native americans with cancer, a population which is susceptible to ALL, but remains understudied. The MUC family seems to have an influence on the development of ALL in the Amerindian population, and especially MUC19 and MUC3A are shown as possible hotspots. In addition, the 11 new variants found point to the need to have their clinical impact analyzed. Keywords: MUC family; ALL; Susceptibility; Native American Populations; Brazil.
Biomarker analysis of first-line sintilimab plus gemcitabine and cisplatin in patients with advanced biliary tract cancers: Results from a phase II study.
Authors: Zhen-gang Yuan, Tian-mei Zeng, Chen-jie Tao, Guang Yang, He-ming Xu, Wei Wei, Xi-yun Chen, Zhuo Cheng, Yu-long Dong, Pei-pei Shang, Cheng Lou, Qin Han, Dong-sheng Chen, Yunjie Song
Journal: Journal of Clinical Oncology (2022)

e16189 Background: The overall efficacy of immunotherapy for advanced biliary tract cancers (BTCs) was still poor, exploring the potential biomarkers associated with tumor response in advanced BTCs may further improve the clinical benefits from immunotherapy. Methods: Twelve patients from a phase 2 clinical trial (ChiCTR2000036652), which evaluated the efficacy and safety of sintilimab (anti-PD-1 antibody), plus gemcitabine and cisplatin as first-line treatment in advanced BTC patients, were included in the current biomarkers analysis. Exploratory points mainly focused on differentiated immune-related gene expression and immune pathway signatures using a 289-gene immune-related RNA panel sequencing on baseline tumor samples. Differential gene expression analysis was performed between responders (tumor regression) and non-responders (tumor extension) using Wilcoxon rank-sum test. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures. Results: Twelve patients (8 responders vs. 4 non-responders) who had available clinical response evaluations with RNA-sequencing data on baseline tumor samples were included in the current biomarkers analysis. Differential gene expression analysis revealed a significantly increased CXCL10, CXCL13 expression (p &lt; 0.001) and decreased MAGEA12 expression (p &lt; 0.001) in responder tumors compared with non-responder tumors. Differentiated genes were significantly enriched in cytokine-cytokine receptor interaction and interleukin-17 signaling pathway in responder tumors. Extensive analyses on immune pathway signatures showed that higher expression of IFN-γ-related genes (p = 0.048) and T cell-inflamed genes (p = 0.016) were associated with response to immunocombination therapy. Meanwhile, immune cell types score was also calculated, no notable differences were found between defined groups. Conclusions: Some differentially expressed genes were investigated in responder tumors compared with non-responder tumors. Higher expression of IFN-γ-related genes and T cell-inflamed genes could potentially predict the effect of immunocombination therapy. Potential biomarkers are needed to identify patients who respond to sintilimab plus gemcitabine and cisplatin in a larger validation cohort. Clinical trial information: ChiCTR2000036652.
The impact of HRD in patients with pancreatic adenocarcinoma undergoing surgical resection: An updated analysis.
Authors: Gudbjorg Jonsdottir, Asgeir Thor Masson, Laura S. Jacobus, Michelle L. Churchman, Stephen B. Edge, Anne M. Noonan, Michael J. Cavnar, Susanna Varkey Ulahannan, Ibrahim Halil Sahin, Carlos Hou Fai Chan
Journal: Journal of Clinical Oncology (2022)

4132 Background: Limited data is available regarding which mutations in the homologous recombination repair (HRR) pathway beyond BRCA can be targeted with platinum-based chemotherapy in the perioperative setting in patients with pancreatic ductal adenocarcinoma (PDAC). In this updated analysis, we assess the outcome of patients with homologous recombination deficiency (HRD) in response to platinum vs. non-platinum based perioperative chemotherapy in resected PDAC and have included additional variants linked to HRD. Methods: Patients with resectable PDAC, diagnosed between 1999-2020 from the participating members of the Oncology Research Information Exchange Network (ORIEN) were included in the study. Patient’s germline and somatic whole exome sequencing (WES) data were analyzed for known pathogenic and likely pathogenic variants according to ClinVar for the following HRR pathway genes: BRCA1, BRCA2, PALB2, BRIP1, BRAD1, BLM, BAP1, ATM, RAD51C, RAD51, RAD50, RAD54B, CHECK2, NBN, FANCA/B/C/D2/E/F/G, ARID1A, MRE11 and XRCC2. The Kaplan Meier method was used to compare median overall survival (mOS) between patients with and without HRR pathway mutations in response to perioperative platinum vs non-platinum-based chemotherapy. Multivariate cox proportional hazard model was used to calculate HR and 95% CIs adjusting for age, sex and pathologic stage. Results: The ORIEN cohort included 311 patients with resectable PDAC and available WES data. A total of 22 patients (7%) had an HRR pathway mutation. Of these, 8 (36%) received perioperative platinum-based chemotherapy and 9 (41%) a non-platinum based regimen, 4 patients (23%) received no perioperative systemic treatment. Frequency of HRR variants detected: BRCA2 n=8 (2.6%), BRCA1 n=3 (1%), ATM n=2 (0.6%), ARID1A n=1 (0.3%), BRIP1 n=1 (0.3%), CHECK2 n=1 (0.3%), FANCG n=1 (0.3%), PALPB2 n=1 (0.3%), RAD50 n=4 (1.3%), RAD51C n=1 (0.3%). The mOS for patients with HRR mutations exposed to perioperative platinum-based chemotherapy was 3.5 years (95% CI 3.4-NA), patients with HRR mutation but no platinum exposure had a mOS of 1.2 years (CI 0.9-NA). In patients with no HRR mutation exposed to platinum-based chemotherapy mOS was 2.7 years (CI 2.3-3.9) and in those without exposure mOS was 2.9 years, p=0.43. Comparison of risk of death between the 4 groups is demonstrated in the table. Conclusions: There was a trend towards improved survival in patients with PDAC who harbored a HRR pathway mutation and were treated with perioperative platinum-based chemotherapy compared to those with no platinum exposure. Our results highlight the importance of identifying patients with HRD beyond BRCA and the need for large prospective studies in the perioperative setting to further assess their predictive role. [Table: see text]